Novel process for the preparation of roflumilast

ABSTRACT

The invention relates to novel processes for the preparation of high-purity roflumilast.

TECHNICAL FIELD

The present invention relates to a novel, improved process for thepreparation ofN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide(INN: roflumilast).

PRIOR ART

The international patent application WO 95/01338 describes thepreparation of dialkoxy-substituted benzamides, including roflumilast,and the use thereof as PDE4 inhibitors. The international applicationsWO 94/02465 and WO 93/25517 also describe the preparation ofdialkoxy-substituted benzamides. In the International patent applicationWO03/070279 oral dosage forms comprising roflumilast are described. Inthe international patent application WO03/099334 topically applicablepharmaceutical preparations comprising roflumilast are described.Organic Process Research & Development 2, 157-168 (1998) disclosesimproved processes for the preparation of3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (INN:piclamilast).

In the international applications WO 94/02465 and WO 93/25517, thedialkoxy-substituted benzamides are obtained by reacting activatedbenzoic acid derivatives of the general formula

with amines of the general formula R3NH₂. Activated benzoic acidderivatives mentioned are acid halides, especially acid chlorides orelse anhydrides. The reaction may take place in the presence of a base,e.g. of an organic base such as, for example, triethylamine, in thepresence of a cyclic base such as, for example, N-methylmorpholine orpyridine or else in the presence of an alkali metal hydride such as, forexample, sodium hydride, in an Inert solvent such as, for example,tetrahydrofuran, dimethylformamide or dichloromethane.

3-(Cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (INN:piclamilast) is obtained in WO 93/25517 by reacting3-cyclopentyl-4-methoxybenzoic acid, which has been deprotonated withN-methylmorpholine, with 4-amino-3,5-dichloropyridine intetrahydrofuran. In WO 94/02465,3(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (INN:piclamilast) is prepared by mixing together and subsequently melting4-amino-3,5-dichloropyridine and 3-cyclopentyloxy-4-methoxybenzoylchloride.

In the process for preparing roflumilast described in WO 95/01338, asolution of 0.0275 mol of 3-cyclopropylmethoxy-4-difluoromethoxybenzoylchloride in tetrahydrofuran is added dropwise to a suspension of 0.03mol of 4-amino-3,5-dichloropyridine and 0.066 mol of NaH (in mineraloil) in tetrahydrofuran at 15-20° C.

In the improved process described in Organic Process Research &Development 2, 157-168 (1998) for preparing3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (INN:piclamilast), firstly 0.218 mol of KOtBu is added to 0.22 mmol of4-amino-3,5-dichloropyridine at 90° C., and then a solution of 0.2 molof 3-cyclopentyloxy-4-methoxybenzoyl chloride is added. The mixture isboiled under reflux for some time, cooled to 90° C. again and then afurther 0.218 mol of KOtBu is added. This is followed by boiling underreflux again, before the reaction mixture is worked up by methods knownto the skilled person.

None of the processes described in the international applications WO93/25517 and WO 94/02465 for preparing piclamilast, nor the processdescribed in WO 95/01338 for preparing roflumilast, appear to besuitable for the industrial preparation of roflumilast of high purity.

Although the improved process described in Organic Process Research &Development 2, 157-168 (1998) for preparing3-(cyclopentyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (INN:piclamilast) has already been optimized for feasibility on theindustrial scale, when applied analogously to roflumilast it leads tothe formation of more than 3% by weight of the by-productN-(3,5-dichloropyrid-4-yl)-3-cyclopropyl methoxy-4-hydroxybenzamide,which cannot be reduced even by multiple recrystallization.

DESCRIPTION OF THE INVENTION

It has now been found, surprisingly, that the formation of by-products,especially of the abovementioned by-product, can be very substantiallyaverted when an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is reacted with anexcess of the anion of 4-amino-3,5-dichloropyridine.

A first aspect of the invention is therefore a process for thepreparation of roflumilast by reacting the anion of4-amino-3,5-dichloropyridine (1)

with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2),

characterized in that the molar ratio of the employed anion of4-amino-3,5-dichloropyridine to the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is at least 1.5 andat most 3, preferably at least 1.8 and at most 2.7, particularlypreferably at least 2 and at most 2.5 and very particularly preferably2.2.

A⁺ in the formula I is a cation; A⁺ is, for example, an alkali metalcation, preferably the potassium cation. LG in formula 2 is a suitableleaving group, preferably a chlorine atom, a bromine atom or a radicalof the formula OC(O)-1-4C-alkyl. LG is particularly preferably achlorine atom.

1-4C-alkyl in the formula OC(O)-1-4C-alkyl is a straight-chain orbranched alkyl radicals having 1 to 4 carbon atoms. Examples which maybe mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl and methyl radicals.

Reaction of the anion of 4-amino-3,5-dichloropyridine (1) with anactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) can be carried out in all conventional Inert solvents such as,for example, dichloromethane, toluene, xylene, dimethylformamide orN-methylpyrrolidone. The use of dimethylformamide or N-methylpyrrolidoneis preferred. The use of dimethylformamide is very particularlypreferred.

A further aspect of the invention is therefore one of the processesdescribed above for preparing roflumilast, characterized in thatreaction of the anion of 4-amino-3,5-dichloropyridine (1) with anactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) is carried out in a solvent selected from the group ofdichloromethane, toluene, xylene, dimethylformamide orN-methylpyrrolidone, preferably in dimethylformamide orN-methylpyrrolidone and very preferably in dimethylformamide.

The reaction temperatures for the conversion are between 0° C. and theboiling point of the solvent used. The conversion is preferably carriedout at temperatures between 15, and 40° C., very particularly preferablybetween 20 and 30° C.

A further aspect of the invention is therefore one of the processesdescribed above for preparing roflumilast, characterized in thatreaction of the anion of 4-amino-3,5-dichloropyridine (1) with anactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) is carried out at a temperature between 0° C. and the boilingpoint of the Inert solvent used, preferably at a temperature between 15and 40° C. and particularly preferably at a temperature between 20 and30° C.

In the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with anactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) it is possible to add either the anion of4-amino-3,5-dichloropyridine (1) or the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) to the respectiveother reactant. However, the process in which the activated derivativeof 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is added as secondreactant to the anion of 4-amino-3,5-dichloropyridine (1) is preferred.

Activated derivatives of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) may be, for example, the corresponding acid halides, especiallythe acid chloride or else an anhydride [LG then corresponds to Cl, Br orOC(O)-1-4C-alkyl]. The acid halides are preferred in this connection,and the acid chloride is very particularly preferred.

A further aspect of the invention is therefore the process describedabove for preparing roflumilast, characterized in that the activatedderivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is a3-cyclopropylmethoxy-4-difluoromethoxybenzoyl halide, especially3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride.

Strong bases selected from the group of KOtBu, NaOtBu and LiOtBu areparticularly suitable for preparing the anion of4-amino-3,5-dichloropyridine. The use of KOtBu is preferred.

A further aspect of the invention is therefore one of the processesdescribed above for preparing roflumilast, characterized in that a baseselected from the group of KOtBu, NaOtBu or LiOtBu is used to preparethe anion of 4-amino-3,5-dichloropyridine. KOtBu is preferably used.

The molar ratio of employed base to 4-amino-3,5-dichloropyridine is inthis case advantageously in the range from 0.8 to 1.1 and preferably inthe range from 0.9 to 1.0.

A further aspect of the invention is therefore one of the processesdescribed above for preparing roflumilast, characterized in that themolar ratio of employed base to 4-amino-3,5-dichloropyridine in theanion formation is between 0.8 and 1.1, preferably between 0.9 and 1.0.

The activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid is prepared bymethods known to the skilled person.

The corresponding acid chloride is, for example, preferably prepared byreacting 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid with thionylchloride in the presence of catalytic amounts of dimethylformamide in aninert solvent. An example of an inert solvent is toluene or xylene; thechlorination reaction is typically carried out at 70 to 90%.

The roflumilast prepared by the processes described above isdistinguished by a purity of ≧99% by weight. Crystallization fromisopropanol/water (ratio:between 85:15 and 100:0% by volume, preferablybetween 90:10 and 95:5% by volume) allows the purity to be increasedfurther to ≧99.8% by weight.

A further aspect of the invention is therefore one of the processesdescribed above for preparing roflumilast, characterized in that theproduct resulting from the process is recrystallized in a mixture ofisopropanol and water (ratio isopropanol/water:between 85:15 and 100:0%by volume, preferably between 90:10 and 95:5% by volume).

Further aspects of the Invention which should be mentioned are:

Roflumilast prepared by one of the processes described above,characterized in that its purity is ≧99% by weight, preferably ≧99.8% byweight.

Roflumilast prepared by one of the processes described above,characterized in that it contains less than 0.1% by weight, preferably0.05% by weight, of the by-productN-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-hydroxybenzamide.

The processes according to the invention for the preparation ofroflumilast are in particular useful for the large-scale preparation ofroflumilast; high-purity roflumilast can be prepared in a scale of about5 to 500 kg per batch.

Roflumilast prepared by one of the processes described above can be usedin human and veterinary medicine for the treatment and prophylaxis, forexample, of the following diseases: acute and chronic (especiallyinflammatory and allergen-induced) airway disorders of variousetiologies (bronchitis, allergic bronchitis, bronchial asthma,emphysema, COPD); dermatoses (especially of a proliferative,inflammatory and allergic nature) such as, for example, psoriasis(vulgaris), toxic and allergic contact eczema, atopic eczema, seborrhoiceczema, lichen simplex, sunburn, pruritus in the genitoanal region,alopecia greata, hypertrophic scars, discoid lupus erythematosus,follicular and extensive pyodermas, endogenous and exogenous acne, acnerosacea and other proliferative, Inflammatory and allergic skindisorders; disorders based on excessive release of TNF an leukotrienes,e.g. disorders of the arthritic type (rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic states), disorders ofthe immune system (AIDS, multiple sclerosis), types of shock [septicshock, endotoxin shock, gram-negative sepsis, toxic shock syndrome andARDS (adult respiratory distress syndrome)] and generalizedinflammations in the gastrointestinal region (Crohn's disease andulcerative colitis); disorders based on allergic and/or chronic abnormalimmunological reactions in the region of the upper airways (pharyngealspace, nose) and adjacent regions (paranasal sinuses, eyes), such as,for example, allergic rhinitis/sinusitis, chronic rhinitis/sinusitis,allergic conjunctivitis and nasal polyps; but also cardiac disorderswhich can be treated by PDE inhibitors, such as, for example, heartfailure, or disorders which can be treated owing to the tissue-relaxanteffect of PDE inhibitors, such as, for example, erectile dysfunction orcolic of the kidneys and ureters connected with kidney stones; or elsedisorders of the CNS such as, for example, depressions orarteriosclerotic dementia.

The invention therefore further relates to roflumilast prepared by oneof the processes described above for use in the treatment and/orprophylaxis of diseases, especially the diseases mentioned.

The invention also relates to the use of roflumilast prepared by one ofthe processes described above for the production of pharmaceuticalcompositions which are employed for the treatment and/or prophylaxis ofthe diseases mentioned. The disease is preferably an acute or chronicairway disorder (for example asthma, bronchitis, allergic rhinitis,emphysema and COPD), a dermatosis or an arthritic disorder (for examplerheumatoid arthritis, rheumatoid spondylitis and osteoarthritis).

The invention furthermore relates to a method for the treatment ofmammals, including humans, suffering from one of the mentioned diseases.The method is characterized in that a therapeutically effective amountof roflumilast prepared by one of the processes described above isadministered together with conventional auxiliaries and/or excipients tothe mammal with the disease. Preferably the disease is an acute orchronic airway disorder (for example asthma, bronchitis, allergicrhinitis, emphysema and COPD), a dermatosis or an arthritic disorder(for example rheumatoid arthritis, rheumatoid spondylitis andosteoarthritis).

The administration of the pharmaceutical compositions according to theinvention may be performed in any of the generally accepted modes ofadministration available in the art. Illustrative examples of suitablemodes of administration include intravenous, oral, nasal, parenteral,topical, transdermal and rectal delivery. Oral delivery is preferred.

The pharmaceutical compositions are prepared by processes, which areknown per se and familiar to the person skilled in the art. Aspharmaceutical composition, the roflumilast prepared according to one ofthe above-mentioned processes is either employed as such, or preferablyin combination with suitable pharmaceutical auxiliaries and/orexcipients, e.g. in the form of tablets, coated tablets, capsules,caplets, suppositories, emulsions, suspensions, gels or solutions, theactive compound content advantageously being between 0.1 and 95% andwhere, by the appropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) exactly suited to the active compound and/or to thedesired onset of action can be achieved. In the international patentapplication WO03/070279 oral dosage forms comprising roflumilast aredescribed.

The person skilled in the art is familiar with auxiliaries or excipientswhich are suitable for the desired pharmaceutical formulations onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, preservatives,solubilizers, colorants, complexing agents or permeation promoters, canbe used.

For the treatment of disorders of the respiratory tract, the roflumilastprepared according to one of the above-mentioned processes is preferablyalso administered by inhalation in the form of an aerosol; the aerosolparticles of solid, liquid or mixed composition preferably having adiameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.

Aerosol generation can be carried out, for example, by pressure-drivenjet atomizers or ultrasonic atomizers, but advantageously bypropellant-driven metered aerosols or propellant-free administration ofmicronized active compounds from Inhalation capsules.

Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

For the treatment of dermatoses, the roflumilast prepared according toone of the above-mentioned processes is in particular administered inthe form of those pharmaceutical compositions, which are suitable fortopical application. For the production of the pharmaceuticalcompositions, the roflumilast prepared according to one of theabove-mentioned processes is preferably mixed with suitablepharmaceutical auxiliaries and further processed to give suitablepharmaceutical formulations. Suitable pharmaceutical formulations are,for example, powders, emulsions, suspensions, sprays, oils, ointments,fatty ointments, creams, pastes, gels or solutions. In the internationalpatent application WO03/099334 topically applicable pharmaceuticalpreparations comprising roflumilast are described.

The dosage of the roflumilast prepared according to one of theabove-mentioned processes is in the order of magnitude customary for PDEinhibitors, it being possible to administer the daily dose in one ormore dosage units. Customary dosages are disclosed for example inWO95/01338. In general, oral dosage forms contain from 0.01 mg to 5 mg,preferably from 0.05 mg to 2.5 mg, particularly preferably 0.1 mg to 0.5mg of roflumilast per dosage unit. Dosage forms for topicaladministration contain from 0.005 mg to 5 mg, preferably 0.01 mg to 2.5mg particularly preferably 0.1 mg to 0.5 mg of roflumilast per dosageunit. Typically, pharmaceutical compositions of the Invention contain0.01 mg, 0.1 mg, 0.125 mg, 0.25 mg or 0.5 mg of roflumilast per dosageunit.

The following examples serve to illustrate the Invention further withoutrestricting it.

Synthesis of Roflumilast Coupling Step

The potassium salt suspension of the anion of4-amino-3,5-dichloropyridine in DMF (2-2.5 equivalents) is introducedinto a reaction vessel. A solution of3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride (1 equivalent) inDMF is slowly added to this suspension while stirring vigorously at atemperature of 15 to 40° C., preferably 20 to 30° C. After the reactionis complete, water is slowly added while stirring at 15-25° C., and thepH is adjusted to 2-3 with hydrochloric acid.

The solid is centrifuged or filtered, washed with water, resuspended ina sodium hydroxide solution (pH=9-10), centrifuged or filtered again andwashed with water. This moist crude material is, if desired, subjectedto a recrystallization from an isopropanol/water mixture (ratio between85:15 and 100:0, preferably 95:5% by volume). The resulting product iscentrifuged or filtered and dried in vacuo at a temperature notexceeding 60° C.

Synthesis of 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl Chloride

A reaction vessel is charged with toluene, a catalytic amount of DMF(1-5% by weight of the amount of thionyl chloride employed) and 1equivalent of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. Whilestirring, 1 to 4 equivalents of thionyl chloride are slowly added at 70to 90°.

After the reaction is complete, the reaction mixture is concentrated invacuo at 45 to 60° C., and the solvent toluene is replaced by DMF; theresulting 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloridesolution is used without further purification in the subsequent couplingstep.

Synthesis of the Potassium Salt of 4-amino-3,5-dichloropyridine

A reaction vessel is charged with DMF and 4-amino-3,5-dichloropyridine(1 equivalent). While stirring vigorously, potassium tert-butoxide(0.8-1.1, preferably 0.9-1.0 equivalent) is added in portions at atemperature between 15 and 30° C. A suspension of the potassium salt ofthe anion of 4-amino-3,5-dichloropyridine is obtained and is employedwithout further purification for the subsequent coupling step.

Process A: Standard process as described above; synthesis of thepotassium salt of 4-amino-3,5-dichloropyridine using 1 equivalent of4-amino-3,5-dichloropyridine and 1 equivalent of potassiumtert-butoxide.

Process B: Differing from process A in that the potassium salt of4-amino-3,5-dichloropyridine is prepared using 1 equivalent of4-amino-3,5-dichloropyridine and 0.91 equivalent of potassiumtert-butoxide.

Process C: Differing from the standard process in thatN-methylpyrrolidone is used as solvent instead of DMF in the couplingstep and in the preparation, of the potassium salt of4-amino-3,5-dichloropyridine.

Process D: Differing from the standard process in that only 1.8equivalents, instead of 2-2.5 equivalents, of the potassium salt of4-amino-3,5-dichloropyridine are employed in the coupling step.

Process E: Differing from the standard process in that 2.7 equivalents,instead of 2-2.5 equivalents, of the potassium salt of4-amino-3,5-dichloropyridine are employed in the coupling step.

Process F: Differing from the standard process in that the potassiumsalt of 4-amino-3,5-dichloropyridine is prepared using 1 equivalent of4-amino-3,5-dichloropyridine and 1.83 equivalents of potassiumtert-butoxide.

Process G: The improved process described in Organic Process Research &Development 2, 157-168 (1998) for preparing piclamilast (coupling step)is applied analogously to the preparation of roflumilast.

Content of by-product N-(3,5-dichloropyrid-4-yl)-3- Purity afterrecrystallization cyclopropylmethoxy-4-hydroxy- from isopropanol/waterbenzamide Process (data in % by weight) (data in % by weight) A ≧99.8<0.05 B ≧99.8 <0.05 C ≧99.8 <0.05 D ≧99.8 <0.05 E ≧99.8 <0.05 F 96.2 0.8G 95.4 3.47

1-21. (canceled)
 22. Roflumilast prepared by reacting an anion of4-amino-3,5-dichloropyridine (1)

in which A⁺ is a potassium cation, with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2),

in which LG is a suitable leaving group selected from a chlorine atom, abromine atom or a radical of the formula OC(O)-1-4C-alkyl, wherein (a)the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine(1) to the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 1.8and at most 2.7, (b) the reaction of the anion of4-amino-3,5-dichloropyridine (1) with the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out indimethylformamide, (c) the reaction of the anion of4-amino-3,5-dichloropyridine (1) with the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 0° C. and the boiling point of the solvent used,(d) KOtBu is used to prepare the anion of 4-amino-3,5-dichloropyridine(1), and (e) the roflumilast is recrystallized in a mixture ofisopropanol and water, wherein the ratio of isopropanol/water is between85:15 and 100:0% by volume; wherein said roflumilast has a purity levelof greater than or equal to 99.8% by weight.
 23. Roflumilast accordingto claim 22, wherein the molar ratio of the employed anion of4-amino-3,5-dichloropyridine (1) to the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 2 andat most 2.5.
 24. Roflumilast according to claim 22, wherein the molarratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to theactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) is 2.2.
 25. Roflumilast according to claim 22, wherein thereaction of the anion of 4-amino-3,5-dichloropyridine (1) with anactivated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoicacid (2) is carried out at a temperature between 15° C. and 40° C. 26.Roflumilast according to claim 22, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 20° C. and 30° C.
 27. Roflumilast according toclaim 22, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride.
 28. Roflumilastaccording to claim 22, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide.
 29. Roflumilastaccording to claim 22, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 30.Roflumilast according to claim 23, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 15° C. and 40° C.
 31. Roflumilast according toclaim 23, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 20° C. and 30° C.
 32. Roflumilast according toclaim 23, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride.
 33. Roflumilastaccording to claim 23, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide.
 34. Roflumilastaccording to claim 23, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 35.Roflumilast according to claim 24, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 15° C. and 40° C.
 36. Roflumilast according toclaim 24, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with an activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out ata temperature between 20° C. and 30° C.
 37. Roflumilast according toclaim 24, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride.
 38. Roflumilastaccording to claim 24, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is3-cyclopropylmethoxy-4-difluoromethoxybenzoyl bromide.
 39. Roflumilastaccording to claim 24, wherein the activated derivative of3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is a3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid 1-4C-alkyl-ester. 40.Roflumilast according to claim 27, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried outat a temperature between 15° C. and 40° C.
 41. Roflumilast according toclaim 32, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried outat a temperature between 15° C. and 40° C.
 42. Roflumilast according toclaim 37, wherein the reaction of the anion of4-amino-3,5-dichloropyridine (1) with3-cyclopropyl-methoxy-4-difluoromethoxybenzoyl chloride is carried outat a temperature between 15° C. and 40° C.